Heartworm is a parasitic roundworm (especially Dirofilaria immitis and Dirofilaria repens) that is spread from host to host through the bites of mosquitoes. The definitive host is the dog but it can also infect cats, wolves, coyotes, foxes and other animals, such as ferrets, sea lions and even bovines and humans. The parasite is commonly called “heartworm” because the adult reproductive stage of its life cycle resides primarily in the right ventricle of its host where it can live for many years. Heartworm infection may result in serious disease for the host. When a mosquito bites an infected animal, young heartworms called microfilariae enter into that mosquito's system. Within two weeks, the microfilariae develop into infective larvae inside mosquitoes; these infective larvae can be transmitted to another animal when mosquitoes take their next blood meals. Upon entering the dog's circulatory system, the larvae develop and migrate to the dog's heart where they mature and breed. Dirofilaria young, termed “microfilariae,” migrate throughout the hosts' circulatory system, where they may be ingested by a mosquito that feeds upon the infected hosts. The Dirofilaria life cycle is completed when the ingested microfilariae mature into infective larvae in the mosquito. Development of the larvae into adult worms takes about 180 days in dogs.
Dirofilaria immitis presents as white threadlike round worms reaching up to 20 cm for adult males (12-20 cm) and 31 cm for adult females (25-31 cm), with a mean diameter of 1 mm. They are characterised by a relatively smooth cuticle. Heartworms are primarily found in the pulmonary artery in dogs with low parasitic burden (<50 worms). In infestations with high parasitic burden (>50 worms), they may reach the right ventricle, right atrium, and occasionally vena cava. The initial response includes swelling of small pulmonary arteries and blood clotting. The physical presence of the heartworm parasite in the pulmonary artery and right ventricle of the canine heart, and the resulting destruction of tissue, causes respiratory and circulatory problems which can be fatal under conditions of stress or vigorous exercise. Pulmonary hypertension and right-sided congestive heart failure may result. Because it takes a large number of heartworms to clog up blood flow to a significant degree, heartworms can be present inside the heart for up to 2 or 3 years before causing clinical signs. As the disease progresses, lung tissue can be destroyed leading to a worsening cough and liver and kidney damage can occur due to reduced blood flow to these organs. If left untreated, heartworm disease may result in death. After adult heartworms mate and produce immature heartworms, an infected dog which is bitten by an uninfected mosquito will transmit microfilariae to the mosquito, beginning the cycle again. The life cycle of the heartworm is approximately 6 months. The heartworm parasite has also been shown to be the cause of focal lung, liver, eye and cutaneous lesions in man (Hamilton, R. G., et al., Exper. Parasitol., 56:298-313 (1983)).
Heartworm disease due to Dirofilaria immitis and/or Dirofilaria repens continues to cause severe disease and even death in dogs and other animals (cats, bovines, humans, guinea porcine, and ferrets) in many parts of the world, even though safe, highly effective and convenient preventatives have been available for the past two decades. Moreover, the parasite and vector mosquitoes continue to spread into areas where they have not been reported previously. The control of such parasites has long been recognized as an important aspect of human and animal health regimens. Although a number of alternatives to control infestation are in use, these suffer from a variety of problems, including a limited spectrum of activity, the need for repeated treatment (lack of compliance) and, in some rare instances, resistance by parasites.
Currently for curative treatment, only two arsenic derivatives are available for clinically infested dogs, namely thiacetarsamide (Caparsolate® marketed by Abbott laboratories) which is an old medication, with severe adverse effects and melarsomine dihydrochloride (Immiticide® marketed by Merial), which is a more recent drug with fewer side effects.
For chemoprophylaxis, two alternatives are possible to prevent heartworm disease in dogs: daily administration of diethylcarbamazine citrate, or monthly administration of macrocyclic lactones.
Number of macrocyclic lactones have commercialized, for example ivermectin under the name of Ivomec® or Heartgard® marketed by Merial, doramectin (Dectomax®, marketed by Pfizer Animal Health), moxidectin and abamectin (Avomec®, marketed by Merial).
Also, a slow release formulation of subcutaneously injected moxidectin-impregnated lipid microspheres, providing single dose continuous protection in excess of six months, has been marketed by Fort Dodge under the name of Moxidectin SR®, ProHeart 6® or Guardian SR®. However, this product was voluntarily removed from the US market in September 2004 for issues related to safety, and currently has been allowed once again by FDA under a risk minimization and restricted distribution program.
Ivermectin consists of a mixture of two homologous compounds, 22, 23-dihydroavermectin B1a (H2B1a, not less than 80%) and 22, 23-dihydroavermectin B1b (H2B1b, not more than 20%) as described in U.S. Pat. No. 4,199,569. The invention relates to use of said mixture.
Ivermectin has been marketed for treatment of various helminth intestinal parasites including heartworm in animals. Currently approved Heartgard® chewable tablets are administered orally at monthly intervals at the recommended minimum dose level of 6.0 mcg of ivermectin per kilogram (2.72 mcg/lb) of body weight. Heartgard® is available in three dosage strengths for dogs of different weights (68, 136 and 272 mcgs). For other species like swine, cattle, sheep, and horses, ivermectin is available in 10 mg/ml and 2.7 mg/ml injectable form; 0.153 percent and 1.87 percent paste form; 10 mg/ml liquid oral form.
High plasma total ivermectin concentrations are however considered a risk factor for diseases of the nervous systems in dogs. In a 36-clay study in beagle dogs in which ivermectin was administered orally at 0.5 and 2.0 mg/kg of body weight (bw), the concentrations of H2B1a in plasma increased dramatically between days two and eight and reached steady-state after about three weeks. A four-fold increase in the dose resulted in an average eight-fold increase in plasma levels. Such high plasma levels have been observed to cause adverse effects in dogs. In beagle dogs, mydriasis was the most sensitive indicator of toxicity. More severe signs included ataxia and tremors. Deaths were preceded by a comatose state. Approximately 30% of collie dogs were highly sensitive to ivermectin (as estimated from reports from non recommended use of the drug). In a 14-week oral study in beagle dogs (4/sex/group), mydriasis and slight weight loss were observed at 1.0 and 2.0 mg/kg bw. Four dogs in the 2.0 mg/kg bw group developed tremors, ataxia, anorexia and dehydration and were killed prior to the end of the study. The No Observable Effect Levels (NOEL) was 0.5 mg/kg bw. It is now reported that collies are the most frequently affected dogs.
It is known, in humans and in several animal species, that altered expression or function of p-glycoprotein could conceivably allow elevation of brain concentrations of ivermectin and produce severe neurotoxicity. As a consequence of normal dosing regimen for ivermectin, the treated animals necessarily receive a relatively large quantity of the drug which is to remain effective for an extended period. This in turn means that shortly after treatment the animal has a very high concentration of ivermectin in its bloodstream, with this concentration tailing off during the remainder of the period.
Further the currently marketed ivermectin formulations come with certain precautions for usage. The American Heartworm Society (AHS) recognizes the safety-net (or reach-back effect) and adulticidal properties of some macrocyclic lactones, particularly ivermectin. However, heartworm-positive working dogs might be more at risk to develop severe thromboembolism and death. Worsened radiographic and echocardiographic images with greatly restricted exercise suggest that such treatment is contraindicated. Furthermore, even in asymptomatic dogs, it should be administered only with much caution and with examination by a veterinarian at least once every 4-6 months. Likewise, ivermectin must be used with caution in collies and related shepherd dogs that are more susceptible to its neurotoxic effects than other dog breeds.
Accordingly, in order to overcome the foregoing problems, increase the effectiveness of avermectin in eradication of heartworms, and provide for more predictable performance of this drug, there is a need in the art for a dosage form which affords improved absorption and bioavailability of avermectin and more precisely of ivermectin at a lower maximum plasma concentration.
Further the present invention aims to provide novel formulations that are easier to administer and are able to maintain the effective plasma concentration over a prolonged period of time of at least 6 months, 12 months, or at least 18 months to 24 months. Generally topical applications are desirable since many formulations are acceptably safe when used topically, but not when used internally. However, developments of various topical pharmaceutical formulations have posed a number of drawbacks. Some formulations require a large volume to be applied to the animal. This can cause considerable mess and can lead to an unpleasant smell. Additionally, if the dosage of a topical formulation is in a large volume, it can be easily shaken off by the animal, thereby reducing the effectiveness of the formulation. Also, when the animal is a house pet, there is a further complication in that the formulation should be safe for human contact. It should also not lead to staining of furniture, carpeting and the like. Finally, even if safe, topical formulations should not be irritating or lead to rashes, hair loss or exhibit other unpleasant side effects.